The current model of blood-borne metastasis is based on sequential steps starting from movement of primary tumor cells into the bloodstream, survival in the circulation, movement of the tumor cells from the bloodstream into a new tissue, and the founding of a new tumor. Circulating tumor cells (CTCs) have been detected in the majority of epithelial cancers (Yu et al. JCB 2011 192:373) and they hold the key to understanding early dissemination events in cancer. Interestingly, the number of CTCs largely exceeds the number of metastatic lesions in patients, indicating that CTCs are not equally capable of causing metastasis. It is likely that the majority of CTCs die in the bloodstream, with only a minor fraction representing viable metastatic precursors. The identification of the metastatic pool within CTCs has the potential to refine the understanding of cancer metastasis and can permit the development of new agents for the treatment of metastatic human tumors.